Trauma is a common cause of coagulopathy, primarily due to blood loss, hemodilution secondary to fluid resuscitation, and consumption due to injury-induced hyper-coagulation. A high incidence of coagulopathy is found in patients with traumatic brain injury (TBI), even though these patients bleed far less and receive restricted flui resuscitation as compared to patients with injury to the trunk and limbs, suggesting that TBI- associated coagulopathy (TBI-AC) follows a distinct, but poorly defined, pathological course. Brain tissue is highly enriched in key coagulant molecules; but the contribution of these brain-derived molecules to the pathogenesis of TBI-AC is not known. Our preliminary data show that mechanical injury promotes neurons and glial cells to release microparticles that express tissue factor and phosphatidylserine that are active in promoting coagulation. These results led us to hypothesize that 1) injured cerebral tissue releases procoagulant molecules into the circulation through the disrupted blood-brain barrier; 2) these molecules initiate and propagate a hyper-coagulable state in the early stages of TBI; and 3) this exaggerated coagulation is rapidly transited into consumptive coagulopathy. We propose to test these novel hypotheses in an exploratory pilot study by achieving two specific aims. Aim 1 is to measure levels and activity of brain-derived procoagulant molecules in blood samples from patients with only body trauma, isolated TBI and polytrauma with TBI. We will analyze plasma samples from these patients for the presence and activity of the brain-derived procoagulant microparticles and PS-binding scavenger proteins. We will then determine if these results distinguish between TBI patients with and without coagulopathy. Aim 2 is to conduct a complementary mouse study using a model of fluid percussion injury to the brain in order to overcome limitations associated with mechanistically studying TBI-AC in patients. We propose to examine 1) release of procoagulant microparticles from the TBI brain to the circulation and its association with injury to the blood-brain barrier, 2) impact of oxidative modifications on the procoagulant activity of brain phospholipids, and 3) the role of exogenous PS- binding molecules in reducing this procoagulant activity. This exploratory study will examine the feasibility and scientific validity f studying roles of brain-derived procoagulant microparticles in the pathogenesis of TBI-AC. It will lay the foundation for developing a study designed to understand the mechanisms of TBI-AC and identify new therapeutic targets that could reverse the course of coagulopathy with a minimal impact on hemostasis.